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The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype

Nature Reviews Microbiology volume 6, pages 187–198 (2008)Cite this article

Key Points

  • The emergence of drug resistance in pathogenic microorganisms provides an excellent example of evolution that has had profound consequences for human health. As the evolution of drug resistance is outpacing the development of new antimicrobial agents, it is now crucial to understand the evolutionary mechanisms that are involved in order to maintain effective therapeutic strategies.

  • Fungal pathogens pose a particularly acute challenge, owing to the limited number of clinically useful antifungal drugs that are available and the rising incidence and mortality of infections with Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. As tractable model eukaryotes, fungi also provide powerful model systems for the study of evolution, cellular signalling and the genetic architecture of complex traits.

  • This article focuses on the mechanisms that enable the evolution of fungal drug resistance by modulating the trajectory from genotype to phenotype, with an emphasis on the central role of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 regulates the form and function of diverse signal transducers and can function as a capacitor for the storage of genetic variation in a silent state that can be released in response to environmental stress.

  • Hsp90 enables the rapid evolution of resistance to the widely used azole antifungal drugs in Saccharomyces cerevisiae and C. albicans, and is also required for the phenotypic consequences of resistance that is acquired owing to diverse mutations in the genome. The role of Hsp90 in azole resistance is to enable crucial cellular stress responses to the membrane stress that is exerted by the azoles.

  • In Aspergillus species, Hsp90 potentiates basal resistance to the only new class of antifungal drugs to reach the clinic in decades, the echinocandins. The role of Hsp90 in echinocandin resistance is to enable specific cellular stress responses to the cell-wall stress that is exerted by the echinocandins.

  • The central mediator of Hsp90-dependent drug resistance is calcineurin, a key regulator of cellular signalling that requires Hsp90 to maintain its stable form and function. Inhibition of calcineurin with FK506 or cyclosporin A phenocopies the inhibition of Hsp90 with geldanamycin or radicicol, thereby reducing the drug resistance of fungi that are separated by ∼1 billion years of evolution. Drug resistance can evolve from Hsp90-dependence to Hsp90-independence by the accumulation of additional mutations that allow the cell to bypass the stress that is exerted by the antifungal drug.

  • Although Hsp90 provides one of the best examples of an explicit mechanism that can alter the relationship between genotype and phenotype and potentiate the evolution of drug resistance, there are other ways in which alterations in the cellular state can affect resistance phenotypes. Fungal prions — proteins that can adopt an altered conformation that is self-perpetuating and are transmitted as a protein-based element of inheritance — can have a profound impact on resistance phenotypes, as can elaboration of the complex architecture of fungal biofilms.

  • The role of Hsp90 in the emergence and maintenance of fungal drug resistance suggests a promising new combination strategy for treating fungal infections. Pharmacological inhibitors of Hsp90 that are well tolerated in humans can block the evolution of drug resistance and abrogate drug resistance in diverse fungal pathogens, and thus may render resistant pathogens responsive to treatment.

Abstract

The emergence of drug resistance in pathogenic microorganisms provides an excellent example of microbial evolution that has had profound consequences for human health. The widespread use of antimicrobial agents in medicine and agriculture exerts strong selection for the evolution of drug resistance. Selection acts on the phenotypic consequences of resistance mutations, which are influenced by the genetic variation in particular genomes. Recent studies have revealed a mechanism by which the molecular chaperone heat shock protein 90 (Hsp90) can alter the relationship between genotype and phenotype in an environmentally contingent manner, thereby 'sculpting' the course of evolution. Harnessing Hsp90 holds great promise for treating life-threatening infectious diseases.

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Figure 1: Antifungal drugs and their targets.
Figure 2: Azole and echinocandin resistance mechanisms.
Figure 3: Hsp90-mediated genetic capacitance.
Figure 4: The role of Hsp90 in fungal drug resistance.
Figure 5: Inhibition of Hsp90 or calcineurin function abrogates drug resistance of pathogenic fungi.

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Acknowledgements

The author thanks L. Whitesell for invaluable comments on the manuscript. Work in the laboratory of L.E.C. is supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund and by a Canada Research Chair in Microbial Genomics and Infectious Disease.

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  1. Department of Molecular Genetics, University of Toronto, Medical Sciences Building, Room 4368, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Leah E. Cowen

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DATABASES

Entrez Genome Project

Arabidopsis thaliana

Aspergillus fumigatus

Candida albicans

Saccharomyces cerevisiae

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Glossary

Persister cell

A metabolically quiescent cell that neither grows nor dies when exposed to cidal concentrations of antimicrobial compounds.

Polyene

A class of antifungal drug that intercalates into ergosterol-containing fungal membranes, thereby forming membrane-spanning channels that lead to the leakage of cellular components and cell death.

Azole

A class of antifungal drug that inhibits fungal cytochrome P45014DM (also known as lanosterol 14α-demethylase), which is encoded by ERG11 and catalyses a late step in the biosynthesis of ergosterol; includes the triazoles (for example, fluconazole, voriconazole and posaconazole) and the imidazoles.

Echinocandin

A class of antifungal drug that interferes with fungal cell-wall biosynthesis by inhibiting β-(1,3)-d-glucan synthase; includes caspofungin and micafungin.

Major facilitator class

A large family of proteins that uses the energy that is provided by the proton motive force of the membrane to transport substrates across the membrane.

ATP-binding cassette family

A member of a large family of proteins that uses the energy that is provided by the hydrolysis of ATP to transport substrates across membranes.

Isochromosome

An abnormal chromosome that possesses a median centromere and two identical arms.

Epigenetic variation

Variation that is caused by heritable changes that are not a result of a change in the DNA sequence.

Immunophilin

A family of cis–trans peptidylprolyl isomerases that was originally studied as a cellular receptor for immunosuppressive drugs, such as cyclosporin A and FK506; includes cyclophilins and FK506-binding proteins.

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Cowen, L. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Microbiol 6, 187–198 (2008). https://doi.org/10.1038/nrmicro1835

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